Functional Dissection of Metabolic-Sensing Proline Hydroxylation Pathways

代谢传感脯氨酸羟基化途径的功能剖析

基本信息

  • 批准号:
    10552306
  • 负责人:
  • 金额:
    $ 38.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2028-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Proline hydroxylation (Hyp) is a fundamental posttranslational modification and regulatory mechanism that are highly responsive to the changes in cellular metabolic conditions. During tumor progression, the rapid proliferation of cancer cells creates a hypoxic microenvironment that inhibits the hydroxyproline-mediated degradation of HIFa proteins and activates hypoxia-response cellular pathways to promote cancer cell survival in hypoxia. In addition to oxygen, the modification enzyme prolyl hydroxylases are also sensitive to the concentration of iron and key mitochondria metabolites including succinate, fumarate, and alpha-ketoglutarate, making the pathway a critical metabolic sensor in cells. Extensive studies have demonstrated that proline hydroxylation regulates protein structural stability, protein-protein interactions, or proteasomal degradation of substrate proteins. Despite its important roles in cell physiology and success in the targeted analysis of individual substrates, system-wide characterization and functional quantification of the pathway have been hindered by the lack of effective tools and strategies for site-specific identification of proline hydroxylation targets. Our overall hypothesis and long-term goal is that systematic characterization of “proline hydroxylome” through the development of functional proteomics approaches will lead to the mechanistic understanding of novel Hyp-mediated metabolic regulations in development and diseases. Moving towards this goal, in the past years, we have established HypDB for functional annotation analysis of the Hyp proteome with the development of a streamlined workflow for systematic analysis of the Hyp substrates in cells and tissues. We have gained extensive experience in biochemical characterization of Hyp targets, the interactome of specific prolyl hydroxylase as well as its crosstalk with other PTM regulatory pathways. To continue our effort, we will expand the HypDB to quantify Hyp dynamics in mouse tissues and develop functional proteomics strategies to identify key Hyp sites in protein structural stability and prolyl hydroxylase targets. We will apply recently developed chemical and biochemical strategies to investigate the crosstalk between proline hydroxylation and other metabolic-sensing modifications in regulating substrate protein degradation and activity. Furthermore, we will study the physiological significance of a new Hyp-mediated epigenetic modification pathway in regulating gene expression and chromatin activity. Overall, we anticipate that the development and application of functional proteomics technology for system-wide analysis of proline hydroxylation proteome will reveal novel metabolic-sensing pathways and potentially lead to paradigm-shifting concepts in the fields of cancer, metabolic diseases, and development.
项目总结

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Avidity-Based Method for the Efficient Generation of Monoubiquitinated Recombinant Proteins.
基于亲和力的方法,用于有效地产生单泛素化的重组蛋白。
Fluorescent Detection of O-GlcNAc via Tandem Glycan Labeling.
  • DOI:
    10.1021/acs.bioconjchem.0c00454
  • 发表时间:
    2020-09-16
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Wu ZL;Luo A;Grill A;Lao T;Zou Y;Chen Y
  • 通讯作者:
    Chen Y
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Yue Chen其他文献

Yue Chen的其他文献

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{{ truncateString('Yue Chen', 18)}}的其他基金

Improved arrhythmia ablation via MR-guided robotic catheterization and multimodal clinician feedback
通过 MR 引导的机器人导管插入术和多模式临床医生反馈改善心律失常消融
  • 批准号:
    10638497
  • 财政年份:
    2023
  • 资助金额:
    $ 38.44万
  • 项目类别:
Shim System for Removing ICD Artifacts from Patient Cardiac MR Images
用于从患者心脏 MR 图像中去除 ICD 伪影的垫片系统
  • 批准号:
    10546727
  • 财政年份:
    2022
  • 资助金额:
    $ 38.44万
  • 项目类别:
MRI-compatible concentric tube robot for intracerebral hemorrhage
用于脑出血的 MRI 兼容同心管机器人
  • 批准号:
    10531943
  • 财政年份:
    2020
  • 资助金额:
    $ 38.44万
  • 项目类别:
MRI-compatible concentric tube robot for intracerebral hemorrhage
用于脑出血的 MRI 兼容同心管机器人
  • 批准号:
    10318651
  • 财政年份:
    2020
  • 资助金额:
    $ 38.44万
  • 项目类别:
Functional Dissection of Metabolic-Sensing Proline Hydroxylation Pathways
代谢传感脯氨酸羟基化途径的功能剖析
  • 批准号:
    10241993
  • 财政年份:
    2017
  • 资助金额:
    $ 38.44万
  • 项目类别:

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